A disturbance of amyloid-β (“Aβ”) homeostasis in Alzheimer's disease (“AD”) leads to the accumulation of this peptide in the form of plaques in the brain (Selkoe, “The Origins of Alzheimer Disease: A is for Amyloid,” JAMA 283:1615-1617 (2000)). Increased production of Aβ peptides or their inadequate clearance can lead to brain accumulation. It has been demonstrated that peptide homologues to Aβ form amyloid fibrils in solution if they reach a critical concentration (Barrow et al., “Solution Conformations and Aggregational Properties of Synthetic Amyloid Beta-Peptides of Alzheimer's Disease. Analysis of Circular Dichroism Spectra,” J. Mol. Biol. 225:1075-1093 (1992)). This process can be effectively promoted by pathological chaperone proteins such as apolipoprotein E (“apoE”), especially its E4 isoform (Wisniewski et al., “Acceleration of Alzheimer's Fibril Formation by Apolipoprotein E in vitro,” Am. J. Pathol. 145:1030-1035 (1994)), ∝1-antichymotrypsin (“ACT”) (Ma et al., “Amyloid-associated Proteins Alpha 1-Antichymotrypsin and Apolipoprotein E Promote Assembly of Alzheimer Beta-protein into Filaments,” Nature 372:92-94 (1994)), or C1q complement factor (Johnson et al., “The Alzheimer's A Beta-peptide is Deposited at Sites of Complement Activation in Pathologic Deposits Associated with Aging and Age-related Macular Degeneration,” Proc. Natl. Acad. Sci. (USA) 99:11830-11835 (2002)). They promote formation of Aβ fibrils, which remain sequestered within the brain and accumulate in the form of plaques (Castano et al., “Fibrillogenesis in Alzheimer's Disease of Amyloid Beta Peptides and Apolipoprotein E,” Biochem. J. 306:599-604 (1995)). Inheritance of the apoE4 isoform has been identified as a major genetic risk factor for sporadic, late-onset AD (Schmechel et al., “Increased Amyloid Beta-peptide Deposition in Cerebral Cortex as a Consequence of Apolipoprotein E Genotype in Late-onset Alzheimer Disease,” Proc. Natl. Acad. Sci. (USA) 90:9649-9653 (1993)) and correlates with an earlier age of onset and greater Aβ deposition in an allele-dose-dependent manner (Schmechel et al., “Increased Amyloid Beta-peptide Deposition in Cerebral Cortex as a Consequence of Apolipoprotein E Genotype in Late-onset Alzheimer Disease,” Proc. Natl. Acad. Sci. (USA) 90:9649-9653 (1993); Rebeck et al., “Apolipoprotein E in Sporadic Alzheimer's Disease: Allelic Variation and Receptor Interactions,” Neuron 11:575-580 (1993)). ApoE is a 34-kDa glycosylated protein existing in three major isoforms: E2, E3, and E4, which differ in primary sequence at two residues. In vitro, all apoE isoforms can propagate the β-sheet content of Aβ peptides promoting fibril formation, with apoE4 being the most efficient (Wisniewski et al., “Acceleration of Alzheimer's Fibril Formation by Apolipoprotein E in vitro,” Am. J. Pathol. 145:1030-1035 (1994); Ma et al., “Amyloid-associated Proteins Alpha 1-Antichymotrypsin and Apolipoprotein E Promote Assembly of Alzheimer Beta-protein into Filaments,” Nature 372:92-94 (1994); Golabek et al., “The Interaction Between Apolipoprotein E and Alzheimer's Amyloid β-peptide is Dependent on β-peptide Conformation,” J. Biol. Chem. 271:10602-10606 (1996)). The importance of apoE to Aβ deposition has also been confirmed in vivo. Crossing APPV717F AD transgenic (“Tg”) mice onto an apoE knock out (“KO”) background, resulted in a substantial reduction of the Aβ load and absence of fibrillar Aβ deposits (Bales et al., “Lack of Apolipoprotein E Dramatically Reduces Amyloid β-peptide Deposition,” Nature Gen. 17:263-264 (1997)).
Approaches under development for treatment of AD focus on (1) inhibition of enzymes responsible for Aβ cleavage (i.e. Aβ secretases), (2) vaccination, and (3) β-sheet breakers (i.e. compound inhibiting Aβ fibrillogenesis by directly binding to Aβ) (Permanne et al., “Reduction of Amyloid Load and Cerebral Damage in a Transgenic Mouse Model of Alzheimer's Disease by Treatment With a β-sheet Breaker Peptide,” FASEB Journal (2002)). Currently, no treatment targeting the pathomechanism of AD and halting progression of the disease is available.
The present invention is directed to overcoming the deficiencies in existing methods of treating AD.